Therapeutic device for the selective cytoreduction treatment of an obstruction in a natural lumen or passage of the human or animal body

ABSTRACT

Therapeutic device intended for the selective cytoreductive treatment of an obstruction in a natural lumen or passage of the human or animal body, said lumen being obstructed by the effect of a local cell proliferation, said device comprising a tubular element, in particular of cylindrical shape, intended to be placed in said natural lumen and sufficiently flexible to conform to said natural lumen, but sufficiently rigid to maintain an artificial channel in said lumen. The tubular element supports lengthwise a medicinal sleeve which is intended to come into line with, and into contact with, the obstruction once the natural lumen has been intubated, and is designed to deliver locally, at least in its outer surface portion, at least one therapeutic agent which is cytoreductive, in particular cytotoxic, through contact with the cells under whose effect said lumen is obstructed.

The present invention relates to the treatment of a natural lumen orpassage located in a filled area, in particular in a solid organ of thehuman or animal body, which lumen provides for the transit orcirculation of a fluid, in particular a body fluid, which is eitherliquid or gaseous, this natural lumen or passage being obstructed by theeffect of a local cell proliferation.

The urinary passages, and in particular the urethra, constitute examplesof natural lumina within the meaning of the present invention.

The expression “local cell proliferation” is understood to mean anybiological process, for example of the benign or malignant tumor type,leading locally to a tissue excess, either organized or unorganized, andprovoking an obstruction, or obstructing the natural lumen or passage inquestion, at the site where said proliferation develops. Benignprostatic hypertrophy, or prostatic adenoma, constitutes one example ofan obstructive cell proliferation of this nature.

The present invention will be introduced, defined and described, by wayof non-limiting example, with reference to the treatment of acute orchronic prostate obstructions in man.

It is presently known to treat prostate obstruction by mechanical means,that is to say without curative action vis-à-vis the cause of theobstruction, and for this purpose various intraurethral prostheses havebeen described or are available on the market. Reference will be made,by way of example, to the prosthesis which is described in documentWO-A-94/18907.

Such prostheses, which are implanted permanently or temporarily, providefor only a palliative treatment of the prostate obstructions.

These prostheses may be poorly tolerated by the patient on account oftheir purely mechanical action, these prostheses being foreign bodieswhich are left in place permanently, or else temporarily but repeatedly.In some cases there may be a risk of infection and of not inconsiderablemigration. These prostheses, when they are permanent, present a risk ofobstruction, either by incrustation (deposition of crystals contained inthe urine) or by hyperplasia inside the prosthesis, as a reaction to theforeign body which the prosthesis represents; this hyperplasia can go sofar as to obstruct certain permanent prostheses.

The object of the present invention is to remedy these disadvantages.

More specifically, the invention relates to a treatment, of anobstruction in a natural lumen, which is limited in time, is of thecurative type, and has a local and selective action.

In accordance with the present invention, a novel therapeutic treatmentdevice is proposed which can be implanted in the natural lumen orpassage to be treated and which comprises:

in a manner known per se, a non-biodegradable tubular element which isdesigned to be placed and retained, in a substantially self-stabilizingmanner, in the natural lumen being treated; this element, which ispreferably of cylindrical shape, is at one and the same timesufficiently flexible to conform to the natural lumen lying against itswall, and sufficiently rigid to maintain an artificial channel, andhence a circulation, in the natural lumen;

in a novel manner, a medicinal sleeve which is supported by the tubularelement and which is positioned along the length of, and around, thelatter, so as to come into line with, and into direct contact with, theobstruction once the natural lumen has been intubated with said tubularelement; this sleeve comprises or incorporates a therapeutic agent whichis cytoreductive, in particular cytotoxic, specifically vis-à-vis thecells of said local cell proliferation, essentially through simple,superficial and solid tissue contact with said cells; this sleeve ismoreover designed to deliver this therapeutic agent at least in itsouter portion.

According to the present invention, the expression “supported by” isunderstood to mean that the medicinal sleeve is present on the tubularelement, either visibly and/or distinct from the latter, or such that itcannot be seen, being held or incorporated in said tubular element, inits material or its constituent elements, over a length and/or at aposition which are predetermined by said tubular element.

According to the present invention, the term “therapeutic” is understoodto mean any treatment of a medicinal and in particular chemical type, inisolation, or complementing another treatment, and permitting local andselective reduction of the obstruction of the natural lumen or passagein question, whether it be the cells lining the wall of said lumen, orthe cells situated deep behind these cells. According to the presentinvention, this treatment of the medicinal type is facilitated orsupplemented by a treatment of the mechanical type, the aim being tomaintain during treatment, and then to reestablish, the flow in thenatural lumen which is disrupted or prevented as a result of theobstruction of this same lumen.

By virtue of the invention, once the therapeutic device has beenarranged in the obstructed natural lumen, the medicinal sleeveselectively delivers the cytoreductive agent to the obstructed part ofthe wall of the natural lumen, and then to the subjacent cellproliferation. As a consequence of this delivery, there is a gradualerosion of the obstructed part of the wall of the natural lumen beingtreated, then of the subjacent tissue responsible for the compression orobstruction of this same lumen, along a front which has the shape of acylindrical envelope, progressing radially outward, in a mannersubstantially concentric with the medicinal sleeve. This thus leads tothe formation of a channel through the lumen being treated, whichchannel has a transverse dimension at least greater than the normaltransverse dimension of the same lumen. As soon as the contact betweenthe outer surface portion of the medicinal sleeve and the surroundingtissues or cells ceases, the cytoreductive action ceases, it beingunderstood that the latter action can also cease by means of thetherapeutic device according to the invention simply being withdrawnfrom the natural lumen in which it has been positioned.

All in all, this leads to a pharmaceutically induced modeling of thenatural lumen being treated, leaving behind a channel which has as itwere been “molded” on the tubular element of the therapeutic deviceaccording to the invention.

Consequently, as a result of a dual action—both medicinal andmechanical—of the device according to the invention, it is thus possibleto construct a new channel in the obstructed part of any natural lumen,this channel having substantially the same axis and the same shape asthe tubular element which has been used to shape it. Once this newchannel has been created, the device according to the invention iswithdrawn, and the new duct thus obtained acquires an epithelium fromthe upstream and downstream parts of the natural lumen not being treatedwith the medicinal sleeve.

Although the following is one embodiment of the invention among others,it is preferable, on the one hand, for the tubular element to comprisean internal core, which is cylindrical for example, and made of abiocompatible material, in particular a relatively smooth and softmaterial, for example silicone rubber, and, on the other hand, for themedicinal sleeve, distinct from the tubular element and covering thelatter, to be arranged outside the core, and to comprise a biologicallycompatible substrate or support which incorporates the cytoreductivetherapeutic agent.

A therapeutic device according to the invention also affords thefollowing important advantages.

The cytoreductive therapeutic agent is delivered in situ, andspecifically to the cell proliferation generating or having generatedthe obstruction in the natural lumen. Such a local administration of acytoreductive active principle considerably reduces the side effects ormorbidity compared to administration of the same active principlesystemically, for example by the oral route, as regards the treatment ofbenign hypertrophy.

The cytoreductive effect is strictly limited to the obstructed part, andto the exclusion of the surrounding zones of the natural lumen whichremain isolated from the action of the cytoreductive therapeutic agent,since the corrosive effect of said agent on the surrounding tissues isproduced only by mechanical or solid contact, without a liquidintermediary.

The products of tissue or cell degradation are eliminated along thenatural lumen, from which the obstruction has been removed. In general,these products or waste substances can be diluted and evacuated with thebody fluid circulating in the natural lumen being treated.

A therapeutic device according to the invention can be put in place inthe lumen being treated in a simple and non-traumatic way.

As regards the therapeutic treatment of the prostatic portion of theurethra in man, an intraurethral therapeutic device according to theinvention comprises two tubular elements which are intended to bearranged in the urethra, on either side respectively of the sphincter,and are attached to one another by a flexible and deformable connectionmeans which is intended to be held in the orifice of the sphincter. Theupper tubular element supports the medicinal sleeve in the prostaticportion of the urethra, and the lower tubular element does not include amedicinal sleeve. In particular, the medicinal sleeve is positioned, inrelation to the upper tubular element, from a so-called lower end,situated above the bottom end (in relation to the implanted position) ofthe upper tubular element, for example at approximately 10 mm from thisbottom end, to a so-called upper end, situated set back from the top endof the upper tubular element, for example at a distance of between 10and 15 mm from this top end.

By virtue of these supplementary arrangements for an intraurethraldevice, the cytoreductive effect is limited to the obstruction zonewhich extends from the verumontanum to the neck of the bladder, and inparticular to the segment of the prostatic urethra superior to theverumontanum.

The part of the upper tubular element, capable of protruding into thebladder once the implant has been put in place, is not dangerous insofaras this end, which may come into contact with the bladder wall, isdeprived of cytoreductive agent over a certain length.

An intraurethral therapeutic device according to the invention is thusfundamentally distinguished from the intraurethral device which isdescribed in document WO-A-8 903 232 in that:

it makes it possible to treat an obstructed anatomical lumen or duct, inthis case the urethra, present in a solid or filled organ, in this casethe prostate, and not in a general manner an anatomical cavity, in thiscase the bladder, filled with a liquid serving to diffuse thetherapeutic agent;

the support for the therapeutic agent or active principle used isarranged along and around the tubular element, and not at the free endof the latter, which end, according to the present invention, remainsdeprived of said therapeutic agent;

the action of the therapeutic agent is exerted by simple, superficialand solid tissue contact with the cells which are to be destroyed, andnot by diffusion in a liquid, which in turn bathes the wall which is tobe treated; by way of an example, but not exclusively, any therapeuticagent which is not hydrosoluble can be used according to the presentinvention.

And a therapeutic device according to the invention is fundamentallydistinguished from the device which is described in document EP-A-0 164241 in that the tubular element is designed to be self-stabilizing, andnot free in an anatomical cavity, such as the rumen of a ruminant, andto ensure the circulation of a fluid within, and not to contain abiodegradable block in which the therapeutic agent is incorporated.

All these structural and functional differences compared to the priorart identified above justify in particular the fundamental innovationafforded by the present invention, and residing in particular in theidea of pharmaceutically induced modeling of a natural duct or lumen ofa solid or filled organ, as described and defined hereinabove.

The present invention is now described with reference to the attacheddrawing, in which:

FIG. 1 represents a sagittal anatomical section of the urinary passagesof the human male's; a therapeutic device according to the presentinvention is represented in this section, in position in the urethra;

FIGS. 2 and 3 represent a therapeutic device according to the presentinvention, in a frontal view, with its upstream end at the top and itsdownstream end at the bottom, respectively in its configuration beforeimplantation, that is to say ready for use, and in its configurationafter implantation and activation, that is to say in the urethra,although the latter is not represented in FIG. 3;

FIG. 4 represents a cross-sectional view of the device represented inFIG. 2, along the sectional plane IV-IV, taken through the upper andlower tubular elements, respectively, before implantation;

FIG. 5 represents a cross-sectional view of the device represented inFIG. 2, along the sectional plane V-V, taken through the lower and uppertubular elements, respectively;

FIG. 6 represents a cross-sectional view of the device represented inFIG. 3, after implantation and activation, along the sectional planeVI-VI, taken through the lower and upper tubular elements, respectively,of the device;

FIG. 7 represents an axial section of the device represented in FIG. 3,along the sectional plane VII-VII, taken through the lower and uppertubular elements, respectively, of the device;

FIG. 8 represents, in the manner of FIG. 2, another embodiment of adevice according to the invention;

FIG. 9 represents an axial section of the device represented in FIG. 8,along the sectional plane IX-IX;

FIGS. 10 and 11 represent, in axial section, another embodiment of atherapeutic device according to the present invention, beforeimplantation, and, respectively, after implantation and activation inthe urethra, the latter not being represented;

FIGS. 12 and 13 represent two cross sections of a variant embodiment ofa device represented in FIG. 10, before implantation, along thesectional planes XII-XII and XIII-XIII, respectively, identified in FIG.10;

FIGS. 14 and 15 represent cross-sectional views of the devicerepresented in FIGS. 12 and 13, after implantation and activation, alongthe sectional planes XIV-XIV and XV-XV, respectively, identified in FIG.11;

for a variant embodiment of the therapeutic device represented in FIGS.12 to 15, FIGS. 16 and 17 represent views in axial section beforeimplantation, along the sectional planes XII-XII and XIII-XIII,respectively, identified in FIG. 10;

in relation to the sectional planes XII-XII and XIII-XIII, respectively,identified with reference to FIG. 10, FIGS. 18 and 19 represent axialviews of another embodiment of a therapeutic device according to theinvention, before implantation;

FIGS. 20 to 24 represent, diagrammatically and in a frontal view, theurethra before implantation (FIG. 20), the mode of action of atherapeutic device according to the invention in position (FIGS. 21 to23), and the urethra after withdrawal of the same device (FIG. 24);

FIG. 25 represents, in the implanted position in vivo, a therapeuticdevice according to the invention, represented with its withdrawal orsecuring thread;

FIGS. 26 and 27 represent in vivo, and in cross section, along thesectional planes XII-XII of FIG. 10 and XIV-XIV of FIG. 11,respectively, another embodiment of a therapeutic device according tothe invention, before activation of the device (FIG. 26), and afteractivation of the device (FIG. 27).

In accordance with FIG. 1, the urethra 2 extends upward from the urinarymeatus 18 to the neck 19 of the bladder 20. Above the striated muscularsphincter 15, the urethra comprises a prostatic portion 21, consistingof a prostatic segment 210 superior to the verumontanum, and of aprostatic segment 211 inferior to the verumontanum, these segments beingsituated on either side of said verumontanum 30 of the prostate. Belowthe sphincter 15, the urethra comprises, in the direction toward themeatus 18, the membranous segment 221, the bulbar segment 222, theperineal segment 223, and finally the penile segment 224.

As a consequence of any adenoma which has developed in the area of theprostatic portion, the latter is susceptible to obstruction, so that atherapeutic device according to the description given hereinbelow mustbe put in place in the portion 21.

In accordance with FIGS. 2 and 3, this intraurethral therapeutic device1 comprises, in a general manner, two tubular elements 3 and 14 whichare intended to be arranged in the urethra 2 on either side,respectively, of the sphincter 15 and to be attached to one another by aflexible and deformable connection means 16 consisting of a flexible andelastic sleeve which is intended to be held in the orifice of thesphincter 15. The flexible sleeve 16 is in continuity of flow with thetubular elements 3 and 14.

The upper tubular element 3, which is intended to be placed and to beheld in the prostatic portion 21 of the urethra, supports and is coveredby a medicinal sleeve 7 which is positioned along the length of, andaround, said tubular element 3. Consequently, when this tubular element3 is arranged in the prostatic portion 21 of the urethra, the medicinalsleeve 7 comes into line with, and into direct contact with, theprostatic obstruction. This medicinal sleeve 7 comprises a therapeuticagent which is cytoreductive, specifically vis-à-vis the cells of theprostatic cell proliferation, essentially through simple, superficialand solid tissue contact with said cells. The sleeve 7 is furthermoredesigned, especially as regards its support, to deliver this therapeuticagent in its outer surface portion; this surface delivery of thetherapeutic agent can be obtained in all appropriate ways familiar tothe skilled expert, for example quasi-instantaneously, or preferablyslowly, in a delayed manner or gradually, by adapting the nature and/orthe composition of the substrate of the medicinal sleeve, serving as itwere as an excipient for the therapeutic agent proper.

The other, lower, tubular element 14 does not have a therapeutic sleeve,and consequently does not contribute to any therapeutic treatment of theurethra below the sphincter.

The tubular elements 3 and 14, for example of cylindrical shape, aresufficiently flexible to conform to the urethra, in the implantedposition, but are sufficiently rigid to maintain an artificial channel 4in the urethra, ensuring the circulation of the urine.

The therapeutic sleeve 7 is positioned, in relation to the upper tubularelement 3 along its length, so that a so-called lower end is situatedabove the bottom end 3 a of the upper tubular element 3, for exampleapproximately 10 mm from this bottom end, and a so-called upper end issituated set back from, and below, the top end 3 b of the upper tubularelement 3, for example at a distance of between 10 and 15 mm from theabovementioned top end.

As is shown in FIGS. 2 and 3, the top end 3 b of the upper tubularelement 3 is blind, and is perforated 13 in order to ensure the passageof the urine from the bladder 20.

The tubular elements 3 and 14 each comprise a core 6 in the form of atube made of a biocompatible but non-biodegradable material, inparticular a relatively smooth and soft material, for example a siliconerubber.

The medicinal sleeve 7 covers the internal core 6 of the upper tubularelement 3 and is arranged on the outside of the latter. This sleeve 7comprises a biologically compatible substrate incorporating thecytoreductive therapeutic agent. This substrate is expandable and, ifappropriate, radially compressible, so that in the dry state, and beforeimplantation of the device, it adopts a gathered-in and compact,non-expanded configuration, and after implantation and activation, inthe wet or moist state, it adopts an expanded configuration; these twoconfigurations, namely non-expanded and expanded, respectively, arerepresented in FIGS. 2 and 4 and in FIGS. 3 and 6, respectively. Thesubstrate of the sleeve 7 is, for example, a hydrophilic material,.which is expandable under the effect of the biological fluids present orcirculating in the urethra. Examples of an expandable and hydrophilicsubstrate of this kind are the various cellulose materials already usedin the medical sector.

Similarly, but without cytoreductive therapeutic agent, the lowertubular element 14 supports and is surrounded by an outer sleeve 17covering the internal core 6 of said element 14, expandable and, ifappropriate, radially compressible, and consisting, for example, of thesame hydrophilic and expandable, and, if appropriate, biodegradablematerial as that used in the composition of the medicinal sleeve 7.

The medicinal sleeve 7 is covered at the outset, that is to say beforethe implantation of the device, by a protective surface envelope 11which can be broken down and/or biodegraded by tissue contact in situwith the obstructed portion of the urethral duct. More precisely, thisenvelope 11 is capable of retaining the medicinal sleeve 7 in thenon-expanded state before the implantation of the device, and then ofbreaking down, leaving the sleeve 7 free to expand; it is this which isrepresented in FIGS. 2 and 4 and in FIGS. 3 and 6, respectively. Exactlyin the same way, a protective surface envelope 11 which can be brokendown can be used to contain and then to free the outer expandable sleeve17 surrounding the lower tubular element 14.

As is shown in FIGS. 2 and 3, but also in FIG. 25, a withdrawal orsecuring thread 12 is secured to the downstream end of the device, andmore precisely to the bottom end of the lower tubular element 14. Thedownstream end of the thread 12 can moreover be provided with a viewingindicator 50, for example a bead secured on the thread 12, as is shownin FIG. 25.

The medicinal sleeve 7 can incorporate, in addition to the cytoreductiveagent, a bacteriostatic agent, and, if appropriate, all other agentsnecessary for a therapeutic or surgical intervention, for example anagent opaque vis-à-vis X-rays. The cytoreductive agent is chosenpreferably, but not exclusively, from among the antimitotic agents,cytolytic agents, enzymes, hormones, antienzymes, and metal salts, forexample silver salts.

The therapeutic device represented in FIGS. 8 and 9 differs from thatrepresented with reference to FIGS. 2 to 7 in that the sleeves 7 and 17merge with the tubular elements 3 and 14, respectively, and moreprecisely their core 6 as defined above.

The medicinal sleeve 7 is obtained by direct incorporation, at least atthe surface, of the cytoreductive therapeutic agent in the material, forexample the silicone rubber, of the core 6 of the tubular element 3, ina biologically active, elongate zone S, materialized or not.

The protective surface envelope 11 is retained, however, in order toprevent release of the cytoreductive agent in any part of thetherapeutic device not in contact with the obstruction, for exampleprotruding inside the bladder.

The therapeutic device represented in FIGS. 10 and 11 differs from thatrepresented in FIGS. 2 to 7 in that:

the substrate of the medicinal sleeve 7, in its radially non-expandedconfiguration, presents an outer surface inscribed within the remainderof the outer surface of the upper tubular element 3; and in the expandedposition, represented in FIG. 11, the outer surface of the medicinalsleeve 7 emerges from the outer surface of the same tubular element 3;

the same configuration, non-expanded and then expanded, is used for theouter sleeve 17 of the lower tubular element 14.

The therapeutic device represented in FIGS. 12 to 15 differs from thatrepresented with reference to FIGS. 2 to 7 in that the medicinal sleeve7 is limited to a cylindrical surface layer of the substrate, while theremainder of the latter constitutes an expandable connection sleeve 10interposed between the core 6 of the tubular element 3 and the medicinalsleeve 7 proper. The lower tubular element 14 remains unchanged.

The therapeutic device represented in FIGS. 16 and 17 differs from thatrepresented with reference to FIGS. 12 to 15 only insofar as theexpandable medicinal sleeve 7, and also the expandable connection sleeve10, comprise a plurality of radial channels 9 running from the outsidetoward the inside of the substrate, in such a way as to permit andpromote the passage of the bodily liquids or secretions, contributing toor increasing the expansion of the hydrophilic material. These radialchannels are also provided in the protective surface envelope 11, bothon the upper tubular element 3 and on the lower tubular element 14.

The therapeutic device represented with reference to FIGS. 18 and 19differs from that represented with reference to FIGS. 12 to 15 onlyinsofar as it comprises a sheath 8 of a synthetic foam, which is bothcompressible and radially expandable, between the medicinal sleeve 7proper and the core 6 of the upper tubular element 3. With the exceptionof the medicinal sleeve 7, the same arrangement is used for the outersleeve 17 of the lower tubular element 14.

A therapeutic device 1 according to the present invention can be placedin the urethra 2 exactly in the same way as that described in documentWO-A-94/18907, and in particular with the insertion assemblies andsystems described in that document. These means or devices fornon-traumatic insertion are withdrawn as soon as the therapeutic deviceaccording to the present invention has been inserted in the urethra.

Starting with the urethra as represented diagrammatically beforeimplantation in accordance with FIG. 20, and with a therapeutic deviceaccording to the invention in accordance with FIGS. 2 to 7, thetherapeutic treatment of the prostatic adenoma is effected in thefollowing manner.

After non-traumatic insertion, the therapeutic device 1 is positionedrelative to the sphincter 15 by means of simple traction on the securingthread 12. The correct positioning of the therapeutic device can bechecked by ultrasound via the intrarectal route. This leads to theposition represented in FIG. 21.

Upon contact with the natural secretions, the therapeutic device isactivated, and the surface envelope 11 covering the medicinal sleeve 7breaks up upon direct contact with the urethra, so that the urethra andthen the adenoma thus come into direct contact with the outer surface ofsaid sleeve 7. The same is true as regards the lower sleeve 17.

Consequently, the sleeves 7 and 17 expand simultaneously along theirentire length in the area of the lower and upper tubular elements 14 and3, respectively. This expansion of the sleeve 7 increases the contactsurface between the latter and the prostatic urethra, and at the sametime the pressure in the area of the adenoma behind the urethral mucosa.The expansion of the sleeve 17 increases its cross section in the bulbarurethra and improves the longitudinal stability or self-stabilizing ofthe therapeutic device according to the present invention. Thistherefore leads to the configuration of the device as represented insitu in FIG. 22.

The erosion of the urethra 2 and then of the adenoma graduallyprogresses along a substantially cylindrical surface front which iscentered on the medicinal sleeve 7, while the mechanical contact withthe outer surface of the medicinal sleeve 7 allows the cytoreductiveagent to exert its chemical effect on the surrounding tissues. Once theerosion has progressed so far as to give a cavity whose cross section issubstantially equal to that of the sleeve 7, the contact between thecytoreductive agent and the tissues disappears and the therapeuticeffect ceases.

From this moment, the urine easily seeps between the sleeve 7 and thetissues in order to impregnate the hydrophilic substrate, which mayadditionally be biodegradable, for example under the effect of amodification of the pH of the urine. The same degradation is observed inrespect of the sleeve 17. Consequently, the hydrophilic substrate breaksdown, so as to give the configuration represented in FIG. 23.

Finally, the therapeutic device can be withdrawn as soon as it isdesired that the therapeutic effect cease, or when the latter has becomenon-existent on account of the absence of contact between the tissuesand the medicinal sleeve 7. The withdrawal of the device 1 is possibleby means of simple traction on the securing thread 12, so as to resultin the totally treated urethra in accordance with FIG. 24.

If a device in accordance with FIGS. 8 and 9 is used, the expansionphase is omitted.

If a device in accordance with FIGS. 18 and 19 is used, the phase ofabsorption of the sleeves 7 and 17 is omitted.

The use of a therapeutic device according to the invention affords ahigh degree of safety, both passive and active.

With regard to passive safety, as far as the bladder 20 is concernedthere is no direct contact between the medicinal sleeve 7 and the wallof the bladder. Supposing that a part of the sleeve 7 emerges into thebladder and bathes in the urine, in the absence of friction with thetissues the protective envelope 11 will not be broken down or degraded,which fact prevents the release of the cytoreductive agent; and, bydepositing on this envelope, the salts contained in the urine form asupplementary protective layer.

With regard to passive safety in the area of the sphincter, it will benoted, in accordance with the above description, that the latter issituated more than 10 mm from the medicinal sleeve 7. The segment 211inferior to the verumontanum is not intubated by the medicinal sleeve 7and represents a safety barrier for the sphincter 15. The bulbar urethrais never in contact with the medicinal sleeve 7, except momentarily uponinsertion of the device 1. The cytoreductive effect cannot pass deepinto the prostate since, as has already been stated, it is a contacteffect; the latter is limited in terms of depth by the cross section ofthe medicinal sleeve 7, in its expanded configuration.

With regard to active safety, the means for checking the correctpositioning of the device 1 are:

for the physician, at the moment of positioning or during a follow-upcheck, intrarectal and suprapubic ultrasound, for example; later, thedegree of absorption can be evaluated by measuring the diameter of themedicinal sleeve by means of radiography;

for the patient, the thread 12 and its indicator 50 emerging at thelevel of the meatus 18 allow him to check, upon each miction, whetherthe device is in the correct position; its disappearance may cause himto fear an upward migration, demanding an immediate medical check, andits downward migration will lead to dysuria or leakage of urine,likewise demanding a medical check.

All in all, the thread 12 has a triple role:

positioning of the device just after insertion;

indication of the correct positioning of the device, throughout theperiod of treatment;

and means for withdrawing the device at the end of treatment.

It will be possible to prevent any infection by means of incorporating abacteriostatic agent in the medicinal sleeve 7.

A device according to the invention furthermore affords an optimalcost/efficacy ratio, for the following reasons.

The treatment does not require any heavy external instrumentation, sincethe positioning can be performed without general anesthesia, using asimple anesthetic contact gel in the urethra. And simple intrarectalultrasound makes it possible to check that the therapeutic device iscorrectly positioned.

The morbidity associated with the therapeutic device is much lower thanthat associated with surgery and amounts to no more than perinealdiscomfort and transitory aggravation of the prostatism. However, themorbidity will at any rate be limited to the time necessary for theaction of the therapeutic device, since the latter is in place on atemporary basis.

In terms of efficacy, with a device according to the invention, a cavityof suitable shape is created, for example cylindrical, inside theprostate, with a result approximating to that which can be obtained bysurgery.

In all, the invention succeeds in combining maximum efficacy (that ofsurgery), with minimal morbidity (that of a medicament), for a low cost(that of a prosthesis).

According to the present invention, the therapeutic device can have asingle size, since a length of the upper tubular element of the order of70 mm allows the majority of prostatic obstructions to be treated.

The medicinal sleeve can incorporate chemical compounds which arenon-cytostatic, non-cytolytic, such as alpha-blockers, enzymeinhibitors, enzymes or hormones, with a view to reducing the exposure ofthe overall organism to these therapeutic agents and to reducing theirmorbidity, while at the same time maintaining a satisfactory efficacy.

In accordance with FIGS. 26 and 27, the medicinal sleeve 7 and theinternal core 6 are off-centered in relation to each other in such a wayas to destroy the proliferating cells in preferential directions.

A therapeutic device according to the invention also offers thefollowing alternatives:

the flexible connection sleeve 16 between the tubular elements 3 and 14can be openworked, in a manner distributed about its perimeter,especially by longitudinal slots or windows;

the tubular elements 3 and 14 form together with the sleeve 16, in itsflow configuration, a conduit which has an internal cross section whichis substantially constant along the longitudinal direction of thedevice;

the wall of each tubular element 3 and 14, and in particular its core 6,comprises a tubular reinforcement frame, in particular a metal ornon-metal coil, which is for example embedded in the material of eachelement.

1. A therapeutic device intended for substantially fully intracorporealinsertion for treatment of an obstruction in the prostatic portion of amale urethra, comprising: a non-biodegradable element that is designedto be placed and retained in a prostatic portion of the male urethra tomaintain a channel, said element being sufficiently flexible to conformto the urethra, but sufficiently rigid to maintain the channel for urineflow in the prostatic portion, the channel providing for passage ofurine from upstream of the obstruction to downstream of the obstruction;and a cytoreductive agent that causes reduction of the obstruction, saidcytoreductive agent being positioned along said element, so as to treatthe obstruction of the prostatic portion of the male urethra when saidelement is retained in the prostatic portion of the male urethra,wherein the reductive effect is through direct contact of said elementwith cells of the obstruction and even without removing the device fromthe urethra, the reductive effect ceases when the direct contact ceases,and wherein said device further comprises a withdrawal thread and isnon-traumatically removable from the male urethra by said withdrawalthread following treatment of the obstruction.
 2. The device of claim 1,wherein said device is configured to be self-stabilizing.
 3. The deviceof claim 1, wherein said element is of cylindrical shape.
 4. The deviceof claim 1, wherein said cytoreductive agent is selectively reductive tocells of the obstruction.
 5. The device of claim 1, wherein saidcytoreductive agent is cytotoxic to prostatic cells.
 6. The device ofclaim 1, wherein said cytoreductive agent is reductive to urethralmucosal cells.
 7. The device of claim 1, wherein said cytoreductiveagent extends around a perimeter of said element.
 8. The device of claim1, wherein said cytoreductive agent is supported by said element.
 9. Thedevice of claim 1, wherein said cytoreductive agent is distinct fromsaid element and covers said element.
 10. The device of claim 1, whereinsaid cytoreductive agent is located on or in a sleeve, which ispositioned along said non-biodegradable element.
 11. The device of claim1, wherein said cytoreductive agent is incorporated in said element. 12.The device of claim 1, wherein said element comprises (i) a core made ofa biocompatible material and (ii) a biologically active zone, andwherein in the biologically active zone of said element, saidbiocompatible material of said core incorporates said cytoreductiveagent, at least on a surface of said biologically active zone.
 13. Thedevice of claim 12, wherein said core made of biocompatible material ismade of silicone rubber.
 14. The device of claim 1, wherein said elementcomprises an internal core made of a biocompatible material, and saidcytoreductive agent is located on or in a biologically compatiblesubstrate covering at least a portion of said internal core.
 15. Thedevice of claim 14, wherein said internal core is made of siliconerubber.
 16. The device of claim 14, wherein said substrate and saidinternal core are off-centered in relation to one another.
 17. Thedevice of claim 14, wherein said element has an outer surface, whereinsaid substrate is radially expandable, and wherein said substrate has anouter surface that is inscribed within said outer surface of saidelement, and, in the expanded position, emerges from said outer surfaceof said element.
 18. The device of claim 14, wherein said substrate ishydrophilic and expandable under the effect of biological fluids presentor circulating in the obstructed prostatic portion of the male urethra.19. The device of claim 14, further comprising a sheath made of asynthetic foam between said substrate and said internal core.
 20. Thedevice of claim 14, wherein said substrate comprises a plurality ofradial channels.
 21. The device of claim 1, wherein said devicecomprises a bacteriostatic agent.
 22. The device of claim 1, comprisingmeans for checking the correct positioning of said device.
 23. Thedevice of claim 1, comprising an agent which is opaque vis-a-vis X-rays.24. The device of claim 1, wherein said cytoreductive agent is nothydrosoluble.
 25. The device of claim 1, wherein said cytoreductiveagent comprises at least one medicament selected from the groupconsisting of antimitotic agents, cytolytic agents, enzymes, hormones,antienzymes, and metal salts.
 26. The device of claim 1, wherein saidelement comprises a bottom end and a top end, and wherein saidcytoreductive agent is positioned between said bottom end and said topend of said element.
 27. The device of claim 1, wherein saidcytoreductive agent is cytotoxic to urethral mucosal cells.
 28. A methodof treating an obstruction of the prostatic portion of the male urethra,comprising inserting said device of claim 1 into the obstructed portionof the male urethra, thereby opening the obstructed urethra and allowingnormal passage of urine from the bladder.
 29. The method of claim 28,wherein said cytoreductive agent causes a reduction in the obstruction.30. The method of claim 29, further comprising removing said device oncesufficient reduction has occurred that normal urine flow can be achievedin the absence of said device.
 31. The method of claim 28, wherein theobstruction is a tumoral obstruction.
 32. The method of claim 31,wherein said cytoreductive agent erodes the tumoral obstruction.
 33. Themethod of claim 28, further comprising temporarily maintaining saiddevice in the male urethra and then removing said device from the maleurethra.
 34. A therapeutic device intended for substantially fullyintracorporeal insertion for treatment of an obstruction in a naturallumen through which a fluid naturally flows, comprising: anon-biodegradable element that is designed to be placed and retained inthe natural lumen to maintain a channel, said element being sufficientlyflexible to conform to the natural lumen, but sufficiently rigid tomaintain the channel for flow of the fluid in the lumen, the channelproviding for passage of the fluid from upstream of the obstruction todownstream of the obstruction with respect to natural fluid flow; and acytoreductive agent that causes reduction of the obstruction, saidcytoreductive agent being positioned along said element, so as to treatthe obstruction of the natural lumen when said element is retained inthe natural lumen, wherein the reductive effect is through directcontact of said element with cells of the obstruction and, even withoutremoving the device from the lumen, the reductive effect ceases when thedirect contact ceases, and wherein said device further comprises awithdrawal thread and is non-traumatically removable from the naturallumen by said withdrawal thread following treatment of the obstruction.35. The device of claim 34, wherein said device is configured to beself-stabilizing.
 36. The device of claim 34, wherein said element is ofcylindrical shape.
 37. The device of claim 34, wherein saidcytoreductive agent is selectively reductive to cells of theobstruction.
 38. The device of claim 34, wherein said cytoreductiveagent is cytotoxic to cells of a wall of said lumen.
 39. The device ofclaim 34, wherein said cytoreductive agent is reductive to urethralmucosal cells.
 40. The device of claim 34, wherein said cytoreductiveagent extends around a perimeter of said element.
 41. The device ofclaim 34, wherein said cytoreductive agent is supported by said element.42. The device of claim 34, wherein said cytoreductive agent is distinctfrom said element and covers at least a portion of said element.
 43. Thedevice of claim 34, wherein said cytoreductive agent is located on or ina sleeve, which is positioned along said non-biodegradable element. 44.The device of claim 34, wherein said cytoreductive agent is incorporatedin said element.
 45. The device of claim 34, wherein said elementcomprises (i) a core made of a biocompatible material, and (ii) abiologically active zone, and wherein in the biologically active zone ofsaid element, said biocompatible material of the core incorporates saidcytoreductive agent.
 46. The device of claim 45, wherein said core madeof biocompatible material is made of silicone rubber.
 47. The device ofclaim 34, wherein said element comprises an internal core made of abiocompatible material, and said cytoreductive agent is located on or ina biologically compatible substrate covering at least a portion of saidinternal core.
 48. The device of claim 47, wherein said internal core ismade of silicone rubber.
 49. The device of claim 47, wherein saidcytoreductive agent and said internal core are off-centered in relationto one another.
 50. The device of claim 47, wherein said element has anouter surface, wherein said substrate is radially expandable, andwherein said substrate has an outer surface that is inscribed withinsaid outer surface of said element, and, in the expanded position,emerges from said outer surface of said first element.
 51. The device ofclaim 47, wherein said substrate is hydrophilic and expandable under theeffect of biological fluids present or circulating in the obstructednatural lumen.
 52. The device of claim 47, comprising a sheath made of asynthetic foam between said cytoreductive agent and said internal core.53. The device of claim 47, wherein said substrate comprises a pluralityof radial channels.
 54. The device of claim 34, wherein said devicecomprises a bacteriostatic agent.
 55. The device of claim 34, comprisingmeans for checking the correct positioning of said device.
 56. Thedevice of claim 34, comprising an agent which is opaque vis-a-visX-rays.
 57. The device of claim 34, wherein said cytoreductive agent isnot hydrosoluble.
 58. The device of claim 34, wherein said cytoreductiveagent comprises at least one medicament selected from the groupconsisting of antimitotic agents, cytolytic agents, enzymes, hormones,antienzymes, and metal salts.
 59. The device of claim 34, wherein saidelement comprises a bottom end and a top end and wherein saidcytoreductive agent is positioned between said bottom end and said topend of said element.
 60. The device of claim 59, wherein saidcytoreductive agent is positioned between 10 and 15 mm from both saidbottom end and said top end of said element.
 61. A method of treating anobstruction of a natural lumen, comprising inserting said device ofclaim 34 into the obstructed natural lumen so that said element ispositioned in contact with the obstruction, thereby opening theobstructed natural lumen and allowing the normal passage of the fluid.62. A therapeutic device intended for substantially fully intracorporealinsertion for reduction of a pre-existing obstruction in a natural lumenfor flow of a fluid, the lumen being obstructed by the effect of a localcell proliferation, said device comprising: a non-biodegradable elementadapted to be placed and retained in the natural lumen to maintain achannel, and sufficiently flexible to conform to the natural lumen, butsufficiently rigid to maintain the channel for flow of the fluid in thenatural lumen, the channel providing for passage of the fluid fromupstream to downstream of the obstruction with respect to the naturalfluid flow; and a sleeve which is supported by said element and which ispositioned along said element so as to come into contact with theobstruction when said element is retained in the natural lumen, whereinsaid sleeve supports or comprises a cytoreductive agent that causesreduction of the pre-existing obstruction, wherein the reductive effectis through direct contact of said sleeve with cells of the obstructionand, even without removing the device from the lumen, the reductiveeffect ceases when the direct contact ceases.
 63. The device of claim62, wherein said cytoreductive agent is selectively reductive to cellsof the obstruction.
 64. The device of claim 62, wherein said device isan intraurethral therapeutic device and wherein the fluid is urine,which is allowed to pass from upstream to downstream of the obstruction.65. A method of treating a pre-existing obstruction of a natural lumen,comprising inserting said device of claim 62 into the obstructed naturallumen so that said element is positioned in contact with theobstruction, thereby opening the obstructed natural lumen and allowingnormal passage of the fluid.
 66. A method for treating a pre-existingobstruction in the prostatic portion of a male urethra, comprisinginserting said device of claim 64 into the obstructed portion of themale urethra, thereby opening the obstructed urethra and allowing normalpassage of urine.
 67. The method of claim 65, wherein the obstruction isa tumoral obstruction.
 68. The method of claim 67, wherein said agenterodes the obstruction.
 69. A therapeutic device intended forsubstantially fully intracorporeal insertion for treatment of anobstruction in a natural lumen through which a fluid naturally flows,comprising: a non-biodegradable element that is designed to be placedand retained in the natural lumen to maintain a channel, said elementbeing sufficiently flexible to conform to the natural lumen, butsufficiently rigid to maintain the channel for flow of the fluid in thelumen, the channel providing for passage of the fluid from upstream ofthe obstruction to downstream of the obstruction with respect to naturalfluid flow; and a cytoreductive agent that causes reduction of theobstruction, said cytoreductive agent being positioned along saidelement, so as to treat the obstruction of the natural lumen when saidelement is retained in the natural lumen, wherein said cytoreductiveagent is non-selectively cytotoxic, and wherein the reductive effect isthrough direct contact of said element with cells of the obstructionand, even without removing the device from the lumen, the reductiveeffect ceases when the direct contact ceases.
 70. The device of claim69, wherein said natural lumen is the prostatic portion of a maleurethra.
 71. A method of treating an obstruction of a natural lumen,comprising inserting said device of claim 69 into the obstructed naturallumen so that said element is positioned in contact with theobstruction, thereby opening the obstructed natural lumen and allowingthe normal passage of the fluid.
 72. A method for treating anobstruction in the prostatic portion of a male urethra, comprisinginserting said device of claim 70 into the obstructed portion of themale urethra, thereby opening the obstructed urethra and allowing normalpassage of urine.
 73. A therapeutic device intended for substantiallyfully intracorporeal insertion for treatment of an obstruction in anatural lumen through which a fluid naturally flows, comprising: anon-biodegradable element that is designed to be placed and retained inthe natural lumen to maintain a channel, said element being sufficientlyflexible to conform to the natural lumen, but sufficiently rigid tomaintain the channel for flow of the fluid in the lumen, the channelproviding for passage of the fluid from upstream of the obstruction todownstream of the obstruction with respect to natural fluid flow; and acytoreductive agent that causes reduction of the obstruction, saidcytoreductive agent being positioned along said element, so as to treatthe obstruction of the natural lumen when said element is retained inthe natural lumen, wherein said reductive effect is through directcontact of said element with cells of the obstruction and, even withoutremoving the device from said lumen, the reductive effect ceases whenthe direct contact ceases.
 74. The device of claim 73, wherein saidnatural lumen is the prostatic portion of a male urethra.
 75. A methodof treating an obstruction of a natural lumen, comprising inserting saiddevice of claim 73 into the obstructed natural lumen so that saidelement is positioned in contact with the obstruction, thereby openingthe obstructed natural lumen and allowing the normal passage of thefluid.
 76. A method for treating an obstruction in the prostatic portionof a male urethra, comprising inserting said device of claim 74 into theobstructed portion of the male urethra, thereby opening the obstructedurethra and allowing normal passage of urine.
 77. A therapeutic deviceintended for substantially fully intracorporeal insertion for treatmentof an obstruction in a natural lumen through which a fluid naturallyflows, comprising: a non-biodegradable element that is designed to beplaced and retained in the natural lumen to maintain a channel, saidelement being sufficiently flexible to conform to the natural lumen, butsufficiently rigid to maintain the channel for flow of the fluid in thelumen, the channel providing for passage of the fluid from upstream ofthe obstruction to downstream of the obstruction with respect to naturalfluid flow; and a cytoreductive agent that causes reduction of theobstruction, said cytoreductive agent being positioned along a length ofsaid element, so as to treat the obstruction of the natural lumen whensaid element is retained in the natural lumen; wherein saidcytoreductive agent has a continuous surface both around said elementand along said length of said element.
 78. The device of claim 77,wherein said natural lumen is the prostatic portion of the male urethra.79. A method of treating an obstruction of a natural lumen, comprisinginserting said device of claim 77 into the obstructed natural lumen sothat said element is positioned in contact with the obstruction, therebyopening the obstructed natural lumen and allowing the normal passage ofthe fluid.
 80. A method for treating an obstruction in the prostaticportion of a male urethra, comprising inserting said device of claim 78into the obstructed portion of the male urethra, thereby opening theobstructed urethra and allowing normal passage of urine.
 81. A method oftreating an obstruction of a natural lumen through which a fluidnaturally flows, comprising: inserting, in the natural lumen, a devicecomprising a non-biodegradable element and a cytoreductive agentpositioned along said element, so that the element is positioned incontact with the obstruction, wherein the element is sufficientlyflexible to conform to the natural lumen, but sufficiently rigid tomaintain a channel for flow of the fluid in the lumen, said channelproviding for passage of the fluid from upstream of the obstruction todownstream of the obstruction with respect to natural fluid flow;thereby opening the obstructed natural lumen and allowing the normalpassage of the fluid, and wherein the cytoreductive agent causesreduction of the obstruction through direct contact of said element withcells of the obstruction, the reductive effect ceasing when the directcontact ceases even without removal of the device from the lumen. 82.The method of claim 81, wherein said natural lumen is the prostaticportion of a male urethra.
 83. The method of claim 81, wherein saidcytoreductive agent is cytotoxic.
 84. The method of claim 82, whereinsaid cytoreductive agent is cytotoxic to prostatic cells.
 85. The methodof claim 81, wherein said non-biodegradable element is of cylindricalshape.